In recent years, in Korea, the intake of fats from foods has increased due to economic growth and the westernization of eating habits, and metabolic diseases such as hyperlipidemia, obesity, diabetes, hypertension, arteriosclerosis, and fatty liver disease, which are caused by a lack of exercise, have increased.
Diabetes is a kind of metabolic disease in which insulin secretion is insufficient or normal functions are not made (DeFronzo, 1988). Diabetes is characterized by increased blood glucose levels that cause various conditions and syndromes. In the case of diabetes, glucose is excreted with urine. In recent years, due to an increase in obesity, particularly abdominal obesity, the incidence of diabetes has explosively increased.
Worldwide, the number of diabetic patients was estimated to be 170 million in the year 2000 and expected to reach 370 million in the year 2030. However, a recent report showed that the number of diabetes already reached about 350 million worldwide in the year 2008 (Danaei et al., 2011), and thus it is much larger than expected. It was reported that about 80% or more of type 2 diabetic patients were obese, whereas only less than 10% of obese patients were diabetic (Harris et al., 1987). This relationship between diabetes and obesity is because fatty acids are accumulated in beta-cells or insulin-sensitive tissues such as the kidneys, the liver or the heart due to irregular secretion of adipokines and free fatty acids, resulting in lipotoxicity.
If a chronic hyperglycemic condition is not suitably treated, it leads to various pathological conditions in the body. Typically, it increases the risk of retinopathy, renal dysfunction, neuropathy, stroke caused by vascular disorder, kidney or heart diseases, diabetic foot ulcer, and cardiovascular disease. Such complications reduce the quality of life, and eventually reduce the life expectancy of diabetic patients. Thus, to prevent diabetic complications, the effective control of blood glucose levels is essential.
Current methods that are used to control blood glucose levels include lifestyle modification (diet therapy or exercise therapy) and drug therapy. However, diet therapy or exercise therapy is difficult to control and implement strictly, and the therapeutic effect thereof is also insufficient. Thus, most diabetic patients rely on lifestyle modification together with the control of blood glucose levels by drugs such as insulin, insulin secretion stimulators, insulin sensitivity enhancers, and blood glucose level lowering agents.
Insulin that is produced by recombination methods is an essential drug for type 1 diabetic patients and type 2 diabetic patients whose blood glucose levels are not controlled, and it is advantageous for controlling blood glucose levels. However, it has shortcomings, including a fearful feeling for hypodermic needles, difficulty in administration, risk of hypoglycaemia, and an increase in weight.
Meglitinides that are insulin secretion stimulators are drugs having a very quick effect, are taken before meals, and include NovoNorm (repaglinide), Fastic (nateglinide), Glufast (mitiglinide), etc. Insulin sensitivity enhancers are characterized in that they cause little or no hypoglycaemia when being taken alone, and examples thereof include metformin that is a biguanide drug, thiazolidinedione drugs such as Avandia (rosiglitazone), Actos (pioglitazone), etc.
Drugs that were recently developed include GLP-1 agonists developed based on the action of glucagon-like peptide-1, a hormone that stimulates insulin secretion, and examples of the GLP-1 agonists include exenatide and liraglutide. In addition, DPP-4 inhibitors are also recently developed new drugs, which inhibit the activity of DPP-4 (dipeptidyl peptidase-4), an enzyme that rapidly inactivates GLP-1, and typical examples thereof include Januvia (sitagliptin).
However, these drugs were reported to have side effects, including hepatotoxicity, gastrointestinal disorder, cardiovascular disease and carcinogenesis, and the annual cost for treatment of diabetes is also high, and thus is an obstacle in the treatment of diabetes. Indeed, the cost associated with pre-diabetes and diabetes reached about 200 trillion Won in the USA in the year 2007 (Dall et al., 2010), and the cost associated with obesity also reached 150 trillion Won in the USA in the year 2008 (Finkelstein et al., 2009).
Thus, there is an urgent need for the development of drugs, which can be used to treat both diabetes and diabesity by reducing weight and effectively lowering blood glucose levels and, at the same time, and have less side effects.
As a candidate for such drugs, oxyntomodulin has recently received attention. Oxyntomodulin is produced from pre-glucagon, a precursor, and is a peptide that can bind to both glucagon-like peptide-1 (GLP-1) and glucagon receptor to perform dual function. Because of such characteristics, oxyntomodulin has been studied for various purposes, including the treatment of obesity, diabetes, hyperlipidemia and fatty liver disease.
However, oxyntomodulin has a problem in that it should be administered at a high dose, because it has a short half-life in vivo and the activity thereof is insufficient for use in the treatment of obesity, diabetes, hyperlipidemia and fatty liver disease.